Pharmacokinetics of Febuxostat in Healthy Chinese Volunteers

Liu, X.-X.; Liu, R.-J.; Ding, Li; Lin, Yining; Huang, Ningning; Xiao, Huang; Huang, Yajuan; Yang, Jian; Wang, S.-L.

doi:10.1055/s-0032-1321847

Cited by 13 publications

(35 citation statements)

References 10 publications

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“…At the standard daily dosage of 20 mg leflunomide, the average steady-state plasma concentration of A77 1726 is approximately 125 μM (Bohanec Grabar et al, 2009; Rozman, 2002). Pharmacokinetic studies have shown that plasma/serum concentrations of A77 1726 are dose proportional following either single (20–100 mg) or repeated doses (5–25 mg daily) of leflunomide (Li et al, 2002; Mladenovic et al, 1995; Rozman, 2002). Moreover, large inter-individual variability has been observed in the steady-state plasma concentrations of A77 1726 among patients taking therapeutic doses of leflunomide, with an 80-fold concentration range observed between the highest and lowest values (Bohanec Grabar et al, 2009; Chan et al, 2005; Keen et al, 2013; van Roon et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction induced by leflunomide and its active metabolite

et al. 2018

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Leflunomide, an anti-inflammatory drug used for the treatment of rheumatoid arthritis, has been marked with a black box warning regarding an increased risk of liver injury. The active metabolite of leflunomide, A771726, which also carries a boxed warning about potential hepatotoxicity, has been marketed as teriflunomide for the treatment of relapsing multiple sclerosis. Thus far, however, the mechanism of liver injury associated with the two drugs has remained elusive. In this study, cytotoxicity assays showed that ATP depletion and subsequent LDH release were induced in a time- and concentration-dependent manner by leflunomide in HepG2 cells, and to a lesser extent, by A77 1726. The decline of cellular ATP levels caused by leflunomide was dramatically exacerbated when galactose was substituted for glucose as the sugar source, indicating a potential mitochondrial liability of leflunomide. By measuring the activities of immuno-captured mitochondrial oxidative phosphorylation (OXPHOS) complexes, we found that leflunomide and A77 1726 preferentially targeted complex V (F1FO ATP synthase), with IC50 values of 35.0 and 63.7 μM, respectively. Bongkrekic acid, a mitochondrial permeability transition pore blocker that targets adenine nucleotide translocase, profoundly attenuated mitochondrial membrane depolarization, ATP depletion, and LDH leakage induced by leflunomide and A77 1726. Substantial alterations of mitochondrial function at the transcript level were observed in leflunomide-treated HepG2 cells, whereas the effects of A77 1726 on the cellular transcriptome were much less profound. Our results suggest that mitochondrial dysfunction may be implicated in the hepatotoxicity associated with leflunomide and A77 1726, with the former exhibiting higher toxicity potency.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction induced by leflunomide and its active metabolite

et al. 2018

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“…The present work employed the lowest plasma sample volume and had higher sensitivity (LLOQ at 10 ng/mL) compared with most previous reports, with LLOQ ranging from 50 ng/mL to 10 μg/mL (Schmidt et al, ; Chan et al, ; Sobhani et al, ; Rule et al, ). Across a 500‐fold calibration curve the range was adequate to cover the TER plasma concentration range referring to the existing studies (Li et al, ). However, a 1000‐fold calibration curve range was too large for urine concentrations.…”

Section: Resultsmentioning

confidence: 99%

“…Blank human urine and plasma were used to prepare calibration standards and QC samples by diluting corresponding stock solutions. The lower limit of quantification (LLOQ) for TER was selected according to concentrations reported in previous studies (Roussel, ; Li et al, ; Lim et al, ), and ensured a signal‐to‐noise ratio >5. The final plasma concentration of calibration standards for TER and 4‐TMOA were 10, 20, 50, 100, 500, 1000, 2500 and 5000 ng/mL, and concentrations at 25, 400 and 4000 ng/mL were set for QC samples.…”

Section: Methodsmentioning

confidence: 99%

Development of a simple HPLC–MS/MS method to simultaneously determine teriflunomide and its metabolite in human plasma and urine: Application to clinical pharmacokinetic study of teriflunomide sodium and leflunomide

Yao

Liu

Lee

et al. 2019

Biomedical Chromatography

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A simple high-performance liquid chromatography coupled with tandem mass spectrometry method was developed and fully validated to simultaneously determine teriflunomide (TER) and its metabolite 4-trifluoro-methylaniline oxanilic acid (4-TMOA) in human plasma and urine. Merely 50 μL plasma and 20 μL urine were employed in sample preparation using protein precipitation and direct dilution method, respectively. An Agilent Zorbax eclipse plus C 18 column was selected to achieve rapid separation for TER and 4-TMOA within 3 min. Electrospray ionization under multiple reaction monitoring was used to monitor the ion transitions for TER (m/z 269.0 → 159.9), 4-TMOA (m/z 231.9 → 160.0), internal standard teriflunomide-d4 (m/z 273.0 → 164.0) and 2-amino-4-trifluoromethyl benzoic acid (m/z 203.8 → 120.1), operating in the negative ion mode. This method proved to have better accuracy and precision over concentration range of 10-5000 ng/mL in plasma as well as 10-10,000 ng/mL in urine. After a full validation, this method was successfully applied in a pharmacokinetic study of teriflunomide sodium and leflunomide in Chinese healthy volunteers. KEYWORDSHPLC-MS/MS, human plasma and urine, leflunomide, pharmacokinetics, teriflunomide

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“…It has been shown by pharmacodynamic studies that after oral administration, LEF is promptly converted to its active metabolic product, A771726, which has high albumin binding, and is reabsorbed via enterohepatic cycling. The half‐life of LEF is 5–40 days (15 days on average), but previous results have shown that the half‐life of LEF in Chinese patients is only about 8 days . This data suggests that the interval between the administrations of LEF doses could be safely extended.…”

Section: Introductionmentioning

confidence: 86%

“…The half-life of LEF is 5-40 days (15 days on average), 6 but previous results have shown that the half-life of LEF in Chinese patients is only about 8 days. 7 This data suggests that the interval between the administrations of LEF doses could be safely extended. Indeed, it has been reported that weekly administration of 100 mg LEF for RA has the same efficacy as that of the daily administration of 20 mg LEF.…”

Section: Introductionmentioning

confidence: 90%

Efficacy and safety of weekly leflunomide for the treatment of early rheumatoid arthritis: a randomized, multi‐center study

Ren

Chen

et al. 2015

Int J of Rheum Dis

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Aim: The aim of this study was to determine the efficacy and safety of a weekly dose of leflunomide (50 mg/ week) in early rheumatoid arthritis patients with mild or moderate disease activity. Methods:The patients of early rheumatoid arthritis (ERA) with mild or moderate disease activity were randomly selected for inclusion in this study and were assigned to either the treatment group (leflunomide 50 mg/week, LEF50) or the control group (leflunomide 10 mg/day, LEF10). All patients were treated for 24 weeks. Clinical efficacy was assessed using the disease activity score in 28 joints (DAS28) -erythrocyte sedimentation rate (ESR) and European League Against Rheumatism (EULAR) response. A Chi-squared test, Fisher's exact-test and paired t-tests were used to analyze the data.Results: A total of 244 patients who met the inclusion criteria and received at least one medicine dose were analyzed. At the baseline, the DAS28 (ESR) of the ERA patients were 4.41 AE 0.69 in LEF 50 group and 4.52 AE 0.64 in LEF 10 group, respectively. At week 24, the DAS28 (ESR) in two groups ( 2.94 AE 1.10 and 3.02 AE 1.14 ) were significant decreased compare with the baseline, respectively (P<0.01). There was no significant difference in DAS28 (ESR) between the LEF50 and LEF10 groups at week 24. (P > 0.05). At weeks 8, 12 and 24, the EULAR response (good responses + moderate responses) were 47.6%, 58.7% and 59.5%, in the LEF50 group and 43.2%, 49.1% and 53.4% in the LEF10 group, respectively. There was no significant different of EULAR response rates in the two groups at week 8, 12, and 24, respectively (P>0.05). There was no serious adverse events during the study. Conclusion:A weekly dose of 50 mg leflunomide showed similar benefits to a daily dose of 10 mg leflunomide for the treatment of mild-to-moderate early rheumatoid arthritis.

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Pharmacokinetics of Febuxostat in Healthy Chinese Volunteers

Abstract: Compared with the previous study, the pharmacokinetics of febuxostat appeared to be different between Chinese and other races.

Cited by 13 publications

References 10 publications

Mitochondrial dysfunction induced by leflunomide and its active metabolite

Mitochondrial dysfunction induced by leflunomide and its active metabolite

Development of a simple HPLC–MS/MS method to simultaneously determine teriflunomide and its metabolite in human plasma and urine: Application to clinical pharmacokinetic study of teriflunomide sodium and leflunomide

Efficacy and safety of weekly leflunomide for the treatment of early rheumatoid arthritis: a randomized, multi‐center study

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